Cesium carbonate → 2-((2-Chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921853Notes

Reaction equation

HRID 921853 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH:36]([CH2:38][CH2:39][OH:40])[CH3:37])[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:35][C:34]1[C:33]([CH:36]([CH2:38][CH2:39][OH:40])[CH3:37])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867084772-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileHCID 899224133-Amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile

Product 1

HCID 899236462-((2-Chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 53.7%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (218 mg, 0.614 mmol), 3-amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile (138 mg, 0.614 mmol), palladium(II) acetate (41.4 mg, 0.184 mmol), DPPF (34.1 mg, 0.061 mmol), Xantphos (35.6 mg, 0.061 mmol), and cesium carbonate (400 mg, 1.229 mmol) were combined in a 50 ml flask and dioxane (6 mL) was added. The flask was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo. The material was purified by flash column chromatography (0%-50% EtOAc/DCM; 80 g column). 2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (179 mg) was obtained as an orange glass.

Workup

  1. customThe flask was evacuated
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationfiltered through celite
  4. washrinsing with EtOAc
  5. customThe solvent was removed in vacuo
  6. customThe material was purified by flash column chromatography (0%-50% EtOAc/DCM; 80 g column)

Sources & evidence

ORD record
ord-89ee186d837e4a91a346983c007d19bd
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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